EP1778209A1 - Methods and compositions for oral delivery of fts - Google Patents
Methods and compositions for oral delivery of ftsInfo
- Publication number
- EP1778209A1 EP1778209A1 EP05787786A EP05787786A EP1778209A1 EP 1778209 A1 EP1778209 A1 EP 1778209A1 EP 05787786 A EP05787786 A EP 05787786A EP 05787786 A EP05787786 A EP 05787786A EP 1778209 A1 EP1778209 A1 EP 1778209A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dosage form
- oral dosage
- fts
- disease
- disorder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000001475 halogen functional group Chemical group 0.000 claims description 5
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
- C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
- C07C321/28—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
Definitions
- U.S. Patent 5,705,528 teaches farnesylthiosalicyclic acid (FTS) and analogs thereof and their utility as anti-cancer agents.
- U.S. Patent 6,462,086 teaches additional therapeutic utilities of these compounds, namely in connection with treatment of non-malignant diseases, pathological states or other disorders that feature or otherwise include Ras-induced proliferation of cells. The patent also teaches that these compounds are inactive when administered orally, but that this shortcoming can be overcome by making a salt of the compound (i.e., salification), formulating the salt in cyclodextrin, and then preparing a buccal tablet (which will dissolve in the mouth when held against the mucous membrane) .
- a salt of the compound i.e., salification
- FTS and its analogs do not require salification or formulation in cyclodextrin to be active upon oral administration.
- a first aspect of the present invention is directed to an oral dosage form comprising an amount of a Ras antagonist effective to treat a responsive disease or disorder involving abnormal cell proliferation, and a pharmaceutically acceptable carrier other than a cyclodextrin, wherein said Ras antagonist is represented by the formula (I)
- R 1 represents farnesyl, geranyl or geranyl-geranyl
- R 2 is COOR 7 , or CONR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen, alkyl or alkenyl;
- R 3 , R 4 , R 5 and R s are each independently hydrogen, alkyl, alkenyl, alkoxy, halo, trifluoromethyl, trifluoromethoxy, or alkylmercapto;
- X represents S.
- the oral dosage forms are tablets or capsules.
- the Ras antagonist is not in the form of a salt.
- a second aspect of the invention is directed to method of treating a treating a disease or disorder involving abnormal cell proliferation, comprising administering to a human subject in need thereof an oral dosage form comprising an amount of a Ras antagonist effective to treat the disease or disorder, and a pharmaceutically acceptable carrier other than a cyclodextrin, wherein said Ras antagonist is represented by the formula
- R 1 represents farnesyl, geranyl or geranyl-geranyl
- R 2 is COOR 7 , or CONR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen, alkyl or alkenyl
- R 3 , R 4 , R 5 and R 6 are each independently hydrogen, alkyl, alkenyl, alkoxy, halo, trifluoromethyl, trifluoromethoxy, or alkylmercapto; and X represents S.
- Fig. 1 is a graph showing concentrations (ng/mL) of FTS in plasma of mice over time following oral ⁇ e.g., gavage) administration of FTS in a corn oil carrier.
- Fig. 2 is a graph showing concentrations (ng/mL) of FTS in plasma of mice over time following oral (gavage) administration of FTS in aqueous carboxymethylcellulose (CMC) carrier.
- CMC carboxymethylcellulose
- Fig. 3 is a bar graph showing average tumor weight in mice (in grams) following oral (gavage) administration of different amounts of FTS in carboxymethylcellulose, as compared to a control .
- Fig. 4 is a bar graph showing FTS plasma concentration (ng/ml) over 1-24 hours after oral administration of 200 mg/kg of FTS to rats.
- Ras antagonists useful in the present invention are represented by formula I:
- R 1 represents farnesyl, geranyl or geranyl-geranyl
- R 2 is COOR 7 , or CONR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen, alkyl or alkenyl
- R 3 , R 4 , R 5 and R 6 are each independently hydrogen, alkyl, alkenyl, alkoxy, halo, trifluoromethyl, trifluoromethoxy, or alkylmercapto;
- X represents S.
- FTS farnesyl-thiosalicylic acid
- FTS analogs embraced by formula I include 5-fluoro-FTS, 5-chloro-FTS, 4-chloro-FTS and S-farnesyl-thiosalicylic acid methyl ester (FTSME) . Structures of these compounds are set forth below.
- Ras antagonists of formula I may be useful. In preferred embodiments, however, the Ras antagonist is not in the form of a salt (i.e., non- salified) .
- Oral dosage forms useful in the present invention include tablets (e.g., including film-coated, sugar-coated, controlled or sustained release), and capsules, e.g., hard gelatin capsules
- Oral dosage forms may be prepared by mixing the active pharmaceutical ingredient, which in this case are the Ras antagonists of formula I, with one or more appropriate carriers
- compositions e.g., compressing the composition into a tablet or filling into a capsule.
- desired dosage form e.g., compressing the composition into a tablet or filling into a capsule.
- the proviso is that the oral dosage forms do not contain a cyclodextrin.
- excipients useful as bulking agents or diluents, binders, buffers or pH adjusting agents, disintegrants (including crosslinked and super disintegrants such as croscarmellose) , glidants, and/or lubricants include lactose, starch, mannitol, microcrystalline cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, dibasic calcium phosphate, acacia, gelatin, stearic acid, magnesium stearate, corn oil, vegetable oils, and polyethylene glycols, and others known to the pharmaceutical practitioner.
- Coating agents such as sugar, shellac, and synthetic polymers may be employed. Dyes and other colorants may be added as well. See, Remington's Pharmaceutical Sciences, The Science and Practice of Pharmacy, 20th Edition, (2000) .
- the oral dosage forms of the present invention are useful in treating diseases and disorders responsive to the Ras antagonists of formula I, e.g., diseases and disorders characterized or mediated, at least in part, by abnormal ⁇ e.g., uncontrolled) cell proliferation, such as Ras-induced cell proliferation.
- the proliferating cells may be malignant or non- malignant in nature.
- responsive does not require that a therapeutic response would be achieved in each and every patient, but rather what a skilled practitioner would reasonably expect based on existing data from patient populations.
- cancers including breast cancer, colon cancer, glioblastoma, lung cancer (small cell and non-small cell lung cancer) , melanoma, Merkel cell carcinoma, neuroblastoma, neurofibromatosis, ovarian cancer, pancreatic cancer and prostate cancer.
- non-malignant diseases and disorders characterized by or involving abnormal (e.g. , uncontrolled) cell proliferation include liver cirrhosis, restenosis after angioplasty (post-angioplasty restenosis) , atherosclerosis, and graft rejection (e.g., graft-versus-host disease (GVHD)) .
- Other examples include autoimmune diseases such as type-1 diabetes mellitus, systemic lupus erythematosis, rheumatoid arthritis, psoriasis, multiple sclerosis, Guillain-Barre syndrome and primary antiphospholipid syndrome.
- the term "effective amount" refers to a dosage of the Ras antagonist that inhibits disease onset or progression or ameliorates symptom(s) of the disease.
- the typical daily dose is 5 mg to 1000 mg, e.g., 100 mg to 1,000 mg per day, which may be administered once daily or as divided doses two or three times daily.
- the oral dosage forms of the present invention e.g., tablet, hard gelatin capsule, or soft gelatin capsule, typically contains from 5 mg to 500 mg of the Ras antagonist.
- the oral dosage forms contain from 10 mg to 250 mg of active pharmaceutical ingredient.
- the oral dosage forms are typically administered to an individual diagnosed with the disease or disorder, although prophylactic administration may be useful to inhibit onset of a disease or disorder e.g., administration prior to an angioplasty procedure to inhibit onset of restenosis.
- oral dosage forms may be suitably packaged for distribution and sale, including printed instructions for administering them as described herein.
- EXAMPLE 1 Bioavailability of Orally Administered PTS [0022] a. FTS formulated in corn oil.
- FTS 40 mg was dispersed in corn oil (10 ml) . Aliquots of the resulting suspension were administered by gavage to CD-I mice (eighteen) at a dose of 40 mg/ml (at a volume of 10 ml/kg of FTS suspension calculated for actual animal weight) . Blood samples were collected in lithium heparin tubes via the retro-orbital plexus while under CO 2 /O 2 anesthesia at I 7 2, 4, 8, 12 and 24 hours (3 animals at each time point) after dosing. Aliquots (100 ⁇ h) of plasma were mixed with water, pH 11 buffer solution and acetonitrile. After centrifugation, the supernatant was evaporated to dryness .
- FTS (40 mg) was dispersed in 0.5% aqueous carboxymethylcellulose (10 ml) . Aliquots of the resulting suspension were administered by gavage to CD-I mice (eighteen) at a dose of 40 mg/ml (at a volume of 10 ml/kg of FTS suspension calculated for actual animal weight) . Blood samples were collected in lithium heparin tubes via the retro-orbital plexus while under CO 2 /O 2 anesthesia at 1, 2, 4, 8, 12, and 24 hours (3 animals at each time point) after dosing. Aliquots (100 ⁇ L) of plasma were mixed with water, pH 11 buffer solution, and acetonitrile. After centrifugation, the supernatant was evaporated to dryness.
- FTS was dispersed in 0.5% aqueous carboxymethylcellulose at a concentration of 5 mg/ml. On the eleventh day after implantation, mice were segregated into three groups and were given vehicle or FTS suspension by gavage.
- Group 1 Controls, 6 mice received 0.2 ml vehicle daily.
- Group 2 (20 mg/kg FTS, 7 mice) received 0.1 ml FTS suspension daily.
- Group 3 (40 mg/kg FTS, 6 mice) received 0.2 ml FTS suspension daily.
- mice were treated for ten days, and were sacrificed. Tumors were excised and weighed.
- FTS active pharmaceutical ingredient 2000 g
- microcrystalline cellulose 2000 g
- FTS active pharmaceutical ingredient (1000 g) lactose
- FTS active pharmaceutical ingredient (500 g) is uniformly dispersed in a mixture of corn oil (3000 g) , lecithin
- EXAMPLE 7 FTS Capsules (200 mg) [0041] FTS active pharmaceutical ingredient (2841 g) , microcrystalline cellulose (1421 g) , starch (710 g) , and magnesium stearate (29 g) are blended to uniformity and filled into size # 0 hard-shell gelatin capsules, with a fill weight of 0.357 g per capsule. Assuming a 5% loss on material transfers, encapsulation equipment startup and adjustment, approximately 13,000 FTS 200 mg capsules are yielded.
- EXAMPLE 8 FTS Capsules (200 mg)
- FTS active pharmaceutical ingredient (1000 g) and microcrystalline cellulose (125 g) are blended to uniformity and filled into size # 1 hard-shell gelatin capsules, with a fill weight of 0.225 g per capsule. Assuming a 5% loss on material transfers, encapsulation equipment startup and adjustment, approximately 4,750 FTS 200 mg capsules are yielded.
- EXAMPLE 9 FTS Capsules (100 mg)
- FTS active pharmaceutical ingredient (1000 g) and microcrystalline cellulose (125 g) are blended to uniformity and filled into size # 2 hard-shell gelatin capsules, with a fill weight of 0.112.5 g per capsule. Assuming a 5% loss on material transfers, encapsulation equipment startup and adjustment, approximately 9,500 FTS 100 mg capsules are yielded.
- Example 10 FTS Capsules (50 mg)
- FTS active pharmaceutical ingredient (1000 g) and microcrystalline cellulose (125 g) are blended to uniformity and filled into size # 3 hard-shell gelatin capsules, with a fill weight of 0.056 g per capsule. Assuming a 5% loss on material transfers, encapsulation equipment startup and adjustment, approximately 18,000 FTS 50 mg capsules are yielded.
- EXAMPLE 11 Bioavailability of Orally Administered FTS to Rats
- FTS was dissolved in a mixture of corn oil (95%) and ethanol (5%) . Aliquots of the resulting solution were administered to CrI:CD(SD) (IGS)BR rats (twenty-four) at a dose of 200 mg/kg. Blood samples were collected in lithium-heparin- containing tubes via the retro-orbital plexus while under CO 2 /O 2 anesthesia at 1, 2, 4, 8, 12 and 24 hours after dosing. Concentration of FTS at each time point was determined by LC/MS. As shown in Fig.
- mean plasma FTS concentrations were 4454 ng/ml at 1 hour, 4550 ng/ml at 2 hours, 3047 ng/ml at 4 hours, 2216 ng/ml at 8 hours, 685 ng/ml at 12 hours, and 140 ng/ml at 24 hours. These values indicate a high level of oral bioavailability.
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Priority Applications (3)
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PL05787786T PL1778209T3 (en) | 2004-08-18 | 2005-08-18 | Methods and compositions for oral delivery of fts |
EP10004111A EP2218451B1 (en) | 2004-08-18 | 2005-08-18 | Use of FTS for treating malignant disorders |
EP10183723A EP2301528B1 (en) | 2004-08-18 | 2005-08-18 | Use of FTS for treating malignant disorders |
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US60236104P | 2004-08-18 | 2004-08-18 | |
PCT/US2005/029389 WO2006023639A1 (en) | 2004-08-18 | 2005-08-18 | Methods and compositions for oral delivery of fts |
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EP10004111.0 Division-Into | 2010-04-19 |
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EP1778209A1 true EP1778209A1 (en) | 2007-05-02 |
EP1778209B1 EP1778209B1 (en) | 2010-05-05 |
EP1778209B8 EP1778209B8 (en) | 2010-06-16 |
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EP10183723A Not-in-force EP2301528B1 (en) | 2004-08-18 | 2005-08-18 | Use of FTS for treating malignant disorders |
EP05787786A Not-in-force EP1778209B8 (en) | 2004-08-18 | 2005-08-18 | Methods and compositions for oral delivery of fts |
EP10004111A Not-in-force EP2218451B1 (en) | 2004-08-18 | 2005-08-18 | Use of FTS for treating malignant disorders |
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EP10183723A Not-in-force EP2301528B1 (en) | 2004-08-18 | 2005-08-18 | Use of FTS for treating malignant disorders |
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US (4) | US8088756B2 (en) |
EP (3) | EP2301528B1 (en) |
AT (2) | ATE535237T1 (en) |
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DE (1) | DE602005021115D1 (en) |
ES (2) | ES2414861T3 (en) |
MX (1) | MX2007001929A (en) |
PL (1) | PL1778209T3 (en) |
WO (1) | WO2006023639A1 (en) |
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MX2007001929A (en) | 2004-08-18 | 2007-04-17 | Concordia Pharmaceuticals Inc | Methods and compositions for oral delivery of fts. |
US8278349B2 (en) * | 2005-11-28 | 2012-10-02 | Ramot At Tel-Aviv University Ltd. | Cancer treatment using FTS and 2-deoxyglucose |
US8268889B2 (en) | 2006-02-10 | 2012-09-18 | Ramot At Tel-Aviv University Ltd. | Treatment of ovarian cancer |
WO2007144889A2 (en) * | 2006-06-14 | 2007-12-21 | Ramot At Tel Aviv University Ltd. | Treatment of neurofibromatosis |
CA2672839C (en) * | 2006-12-19 | 2012-07-03 | Ramot At Tel Aviv University Ltd. | Treatment of lung cancer with s-farnesylthiosalicylic acid and analogs thereof |
JP2013508458A (en) * | 2009-10-26 | 2013-03-07 | ラモット・アット・テル−アヴィヴ・ユニヴァーシティ・リミテッド | Cancer treatment using a combination of FTS and HDAC inhibitor |
CN103906518B (en) * | 2011-10-07 | 2020-03-13 | 派西斯治疗有限责任公司 | Malignant and non-malignant disease treatment using RAS antagonists |
US9738614B2 (en) | 2011-10-07 | 2017-08-22 | Pisces Therapeutics, Llc | Malignant and non-malignant disease treatment with Ras antagonists |
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US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
IL107587A (en) * | 1993-11-12 | 1998-08-16 | Univ Ramot | Farnesyl geranyl or geranyl-geranyl derivatives pharmaceutical compositions containing them and methods for their preparation |
AU2859499A (en) * | 1998-03-27 | 1999-10-18 | Chong Kun Dang Corporation | (streptomyces) sp. producing tautomycetin and immunosuppressant comprising tautomycetin as active ingredient |
EP1187605A4 (en) * | 1999-06-18 | 2004-05-26 | Thyreos Corp | Non-malignant disease treatment with ras antagonists |
US20020115696A1 (en) * | 1999-06-18 | 2002-08-22 | Yoel Kloog | Treatment of post-angioplasty restenosis and atherosclerosis with ras antagonists |
EP1325116A2 (en) * | 2000-10-04 | 2003-07-09 | RAMOT UNIVERSITY AUTHORITY FOR APPLIED RESEARCH & INDUSTRIAL DEVELOPMENT LTD. | Isoprenoid-dependent ras anchorage (idra) proteins |
US20020169183A1 (en) * | 2001-03-08 | 2002-11-14 | Villar Hugo O. | Acridines as stimulators for Fas-mediated apoptosis |
WO2002097114A2 (en) * | 2001-05-29 | 2002-12-05 | Sirna Therapeutics, Inc. | Nucleic acid treatment of diseases or conditions related to levels of ras, her2 and hiv |
CA2515519A1 (en) | 2003-03-20 | 2004-09-30 | Universite Catholique De Louvain | Medical use of ras antagonists for the treatment of capillary malformation |
US20070054886A1 (en) | 2003-05-23 | 2007-03-08 | Ramot At Tel Aviv University, Ltd. | Ras antagonists for treating neurodegenerative disorders |
EP1656129A4 (en) * | 2003-08-22 | 2009-03-11 | Univ Virginia | Blockade of mtor to prevent a hormonal adaptive response |
MX2007001929A (en) * | 2004-08-18 | 2007-04-17 | Concordia Pharmaceuticals Inc | Methods and compositions for oral delivery of fts. |
US8278349B2 (en) | 2005-11-28 | 2012-10-02 | Ramot At Tel-Aviv University Ltd. | Cancer treatment using FTS and 2-deoxyglucose |
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US20150191426A1 (en) | 2015-07-09 |
EP2301528A1 (en) | 2011-03-30 |
US8088756B2 (en) | 2012-01-03 |
MX2007001929A (en) | 2007-04-17 |
CA2577310A1 (en) | 2006-03-02 |
US20090226512A1 (en) | 2009-09-10 |
WO2006023639A1 (en) | 2006-03-02 |
CA2577310C (en) | 2011-01-11 |
ATE466574T1 (en) | 2010-05-15 |
EP1778209B8 (en) | 2010-06-16 |
PL1778209T3 (en) | 2010-10-29 |
EP2218451B1 (en) | 2011-11-30 |
ES2414861T3 (en) | 2013-07-23 |
US20160271089A1 (en) | 2016-09-22 |
EP1778209B1 (en) | 2010-05-05 |
EP2218451A1 (en) | 2010-08-18 |
ES2343737T3 (en) | 2010-08-09 |
ATE535237T1 (en) | 2011-12-15 |
US20120082722A1 (en) | 2012-04-05 |
DE602005021115D1 (en) | 2010-06-17 |
EP2301528B1 (en) | 2013-04-03 |
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